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Molecules structurally and electrostatically similar to a given ligand might provide similar structure/activity relationships Bostrom J et al., J. Med. Chem., 2006 Screening of ligands structurally and electrostatically similar to DOP Study of their binding to a-synuclein through MD simulations Aim of the work

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Discussion carboxy-terminal truncated alpha-syn proteins aggregate faster than the full- length molecule (Murray A. et al., Biochemistry, 2003) Proteolysis has also a role related to C-terminal peptide production? homology with chaperon family (Beyer K., Acta Neuropathol. 2006) Regulation of aggregation due to acidic net charge and to formation of intramolecular contacts (Hoyer W. et al., Biochemistry, 2004) Binding to other proteins or cationic compounds Differential expression of the splicing variant could be related to disease susceptibility, having a protecting role

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In particular, Alanine map [a] shows a high correlation, with a strong minimum centered at negative values, typical of α helix and in lower extent less positive values. Proline residue possesses a spread map [b], showing many positive values and highlighting the left-handed helix dihedrals of Poly-L-proline II conformation. The map of methionine, recently reported to interplay protein–protein interactions20, shows an extra–diagonal peak at [+0.15, +0.03] values of chirality index, as inferred from Figure 2[c], which is absent in the cysteine map of Figure 2[d].

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Once all the correlation maps of native chirality are obtained, we have used them for calculating a quantity to discriminate folded from unordered structures, as expressed in the following:kT NGdataset Fold factor = NG i=1 logP(Gi+1,Gi,AA)(1)where NG is the number of chirality indexes along a protein backbone, dataset refers to both Xray and NMR protein structures and kT is 0.6 Kcal/mol at 300 K. P(Gi+1,Gi) is the conventional joint probability of finding residue i + 1 and i, with Gi+1 and Gi values, in the correlation maps of native chirality. Since we are summing energy quantity, the probability taken into account are not conditional, like those reported in Figure 2 [a]-[d], but normalized as conventional joint probability.

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Random structures of lysozyme, instead, show high values, whose spread entity depends on how many residues do not possess Gi, Gi+1 values in the correlation map of native chirality for a given amino acid i and thus on how many residues adopt disfavored chirality values. Supporting its effectiveness, the NMR structure of lysozyme (1E8L) shows a low value of fold factor, comparable to that one of SCOP classes. Moreover, an intriguing result was found by analyzing structures of the intrinsically disordered gamma- subunit of cGMP phosphodiesterase (pdb code 2JU4) as the values of the fold factor are found to be spread out and to have positive energies, in accordance with the recent contribution of Liu et al.21. The fold factor of this intrinsically disordered protein is lower than those found in random lysozyme, which indicates a dynamical but not random conformational ensemble.